The complement system is a collection of proteins that constitute a central component of the immune system involved in both innate and adaptive immunity. One function of the complement system is host-defense and the destruction of pathogens, but under certain conditions complement is aberrantly activated, resulting in the destructive force of the complement system being redirected toward self-tissue. This pathological activation of complement is, and will continue to be, my primary research focus. The over-arching goals of my activities are to better understand complement-mediated injury mechanisms, and to develop safe and effective therapeutics based on targeted inhibition of complement. Currently, and for the foreseeable future, my focus will be to investigate how complement is activated, how it propagates injury, and how it modulates repair following stroke, traumatic brain injury (TBI), and vascularized composite allograft transplantation. These are all areas of research highly relevant to Veteran health and healthcare. An added theme throughout these investigations will continue to be the development and characterization of complement inhibitors, for both therapeutic application and for use as tools to investigate complement-dependent disease mechanisms under clinically relevant conditions. A particular focus will be the development of injury-site targeted complement inhibitors that provide safer and more effective option than systemic complement inhibition. Some of the approaches developed in the laboratory are in commercial development. More specifically, current and planned research activities are: Traumatic Brain Injury: 1. Investigate how the different complement pathways and activation products contribute to neuroinflammation and promote neurodegeneration after TBI. 2. Investigate the spatiotemporal pattern of complement deposition after TBI and the relationship with neuroinflammatory markers in complement-sufficient and complement-inhibited brains. 3. Investigate the role of a complement-microglial axis in the neurodegenerative loss of neurons and synapses after TBI. 4. investigate neuroinflammation-mediated neurodegeneration and cognitive decline in chronic traumatic brain injury. 5. Investigate visual dysfunction as it relates to TBI. Stroke: 1. Investigate the effects of age and smoking on acute and chronic complement-dependent neuroinflammation after stroke, and investigate the effect of complement modulation in the setting of age and smoking co-morbidities. 2. Investigate how complement and a modified neuroinflammatory response induced by age and cigarette smoke exposure interact with the current standard of care reperfusion therapies and rehabilitation. 3. Investigate complement inhibition as a chronic treatment strategy for stroke, and the role of complement in both injury and repair. 4. Investigate the correlation between systemic complement activity and serum levels of complement activating natural IgM antibodies with stroke outcomes in acute stroke patients with co-morbidities. Vascularized composite allograft transplantation: Use mouse models of limb transplantation to: 1. Investigate the role of complement and donor brain death in ischemia reperfusion injury to grafts. 2. Develop and characterize a novel dual function targeting approach for delivery of complement inhibitors to vascularized composite allograft. 3. Investigate how brain death, complement and early allograft injury affect acute vascularized composite allograft rejection and parameters of required immunosuppressive treatment. 4. Investigate how complement and alloimmunity, and their modulation, affect hindlimb functional recovery in the context of immunosuppressive treatment. 5. Develop a novel approach to prevent graft rejection while minimizing or eliminating the need for systemic immunosuppression.